Retinal Neovascular Disorders: Mouse Models for Drug Development Studies

Neovascularization is a hallmark of several eye diseases leading to visual impairment, and its epidemiological impact is substantial (Lee et al. 1998). In retinal degenerative disease models, neovascularization is the process by which the choroid and/or retina become infiltrated with new blood vessels. In retinal neovascularization (RNV), sprouting retinal vessels penetrate the inner limiting membrane (ILM) and grow into the vitreous, and in some cases, grow through the avascular outer retina into the subretinal space (Campochiaro 2000). Numerous clinical and ­experimental observations indicate that ischemia (or hypoxia) is the driving force behind RNV (Michaelson and Steedman 1949). Occlusion of retinal vessels leading to ischemia is a feature of diseases with RNV, including diabetic retinopathy (DR) and retinopathy of prematurity (ROP) (Campochiaro 2000)

Spatial learning and long-term memory impairments in RasGrf1 KO, Pttg1 KO, and double KO mice

Background: RasGrf1 is a guanine-nucleotide releasing factor that enhances Ras activity. Human PTTG1 is an oncoprotein found in pituitary tumors and later identified as securin, a protein isolated from yeast with a reported role in chromosome separation. It has been suggested that RasGrf1 is an important upstream component of signal transduction pathways regulating Pttg1 expression and controlling beta cell development and their physiological response. At memory formation level, there are contradictory data regarding the role of RasGrf1, while Pttg1 has not been previously studied. Both proteins are expressed in the mammalian hippocampus, which is one of the key brain areas for spatial learning and memory. Objective: The aim of this work was to study a potential link between RasGrf1 and Pttg1 in memory formation. Method: Spatial learning and memory test in the Pttg1 KO, RasGrf1 KO, and Pttg1-RasGrf1 double KO and their correspondent WT mice using a Barnes maze. Results: In comparison with the WT control mice, Pttg1 KO mice learned how to solve the task in a less efficient way, suggesting problems in memory consolidation. RasGrf1 KO mice performance was similar to controls, and they learned to use the best searching strategy. Double KO mice reached a better spatial learning level than WT. Conclusion: A role for Pttg1 in memory consolidation/formation is suggested, while our RasGrf1 KO mice do not show hippocampus associated memory defects

Neovascularization, Enhanced Inflammatory Response, and Age-Related Cone Dystrophy in the Nrl−/−Grk1−/− Mouse Retina

These morphologic and electrophysiological studies demonstrate that the loss of a functional Grk1 on the rodless, enhanced S-cone Nrl null background exacerbates age-related cone dystrophy in a light-independent manner. Based on detailed DNA analysis from the retinas, the authors discovered that retinal degeneration is mediated, in part, through the inflammatory response pathway, which leads to pronounced retinal neovascularization

Pituitary tumor-transforming gene 1 regulates the patterning of retinal mosaics

Neurons are commonly organized as regular arrays within a structure, and their patterning is achieved by minimizing the proximity between like-type cells, but molecular mechanisms regulating this process have, until recently, been unexplored. We performed a forward genetic screen using recombinant inbred (RI) strains derived from two parental A/J and C57BL/6J mouse strains to identify genomic loci controlling spacing of cholinergic amacrine cells, which is a subclass of retinal interneuron. We found conspicuous variation in mosaic regularity across these strains and mapped a sizeable proportion of that variation to a locus on chromosome 11 that was subsequently validated with a chromosome substitution strain. Using a bioinformatics approach to narrow the list of potential candidate genes, we identified pituitary tumor-transforming gene 1 (Pttg1) as the most promising. Expression of Pttg1 was significantly different between the two parental strains and correlated with mosaic regularity across the RI strains. We identified a seven-nucleotide deletion in the Pttg1 promoter in the C57BL/6J mouse strain and confirmed a direct role for this motif in modulating Pttg1 expression. Analysis of Pttg1 KO mice revealed a reduction in the mosaic regularity of cholinergic amacrine cells, as well as horizontal cells, but not in two other retinal cell types. Together, these results implicate Pttg1 in the regulation of homotypic spacing between specific types of retinal neurons. The genetic variant identified creates a binding motif for the transcriptional activator protein 1 complex, which may be instrumental in driving differential expression of downstream processes that participate in neuronal spacing

Mouse models for cone degeneration

Loss of cone vision has devastating effects on everyday life. Even though much effort has been made to understand cone physiology and pathophysiology, no successful therapies are available for patients suffering from cone disorders. As complex retinal interactions cannot be studied in vitro, utilization of different animal models is inevitable. Due to recent advances in transgenesis, mice became the most popular animal model to study human diseases, also in ophthalmology. While there are similarities in retinal anatomy and pathophysiology between mice and humans, there are also differences, most importantly the lack of a cone-rich macula in mice. Instead, cones in mice are rare and distributed over the whole retina, which makes the analysis of cone pathophysiology very difficult in these animals. This hindrance is one of the reasons why our understanding of rod pathophysiological processes is much more advanced. Recently, however, the sparseness of cones was overcome by the generation of the Nrl (- / -) mouse that expresses only cone photoreceptors in the retina. This paper will give a brief overview of some of the known mouse models to study cone degeneration and discuss the current knowledge gained from the analysis of these models